Structure of three tandem filamin domains reveals auto-inhibition of ligand binding

Journal article

Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IfFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 Å resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangemetn, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a β-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin β-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure.

Authors: Lad, Y; Kiema, T; Jiang, P; Pentikäinen, O; Coles, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Publishing Group
• Journal: EMBO Journal More from this journal
• Volume: 26
• Issue: 17
• Pages: 3993-4004
• Publication date: 2007-09-01
• Edition: Publisher's version
• DOI: 10.1038/sj.emboj.7601827
• ISSN: 1460-2075
• Language: English
• Keywords: X-ray crystallography; integrin; cell adhesion; cytoskeleton; filamin
• Subjects: Biochemistry